Until recently, local stem cells were thought to be the sole sources for epithelial repopulation following lung injury. However, an increasing body of data indicates a role for bone marrow derived stem cells (BMSCs) in this process. The scant literature in this area has been largely anecdotal. To date, no study has systematically analyzed the conditions necessary for stem cell to lung engraftment, or even confirmed that these marrow derived cells are functional. Asking these questions is important because, if answered, they will yield information on how to use BMSCs as a renewable pool of pneumocyte precurors and open up new horizons of treatment for currently intractable respiratory disorders. Such a goal would include use of allogeneic marrow transplant or even genetically modified/peripherally mobilized autologous BMSCs to treat inherited or acquired diseases of the respiratory tract such as alpha-1 antitrypsin deficiency or pulmonary fibrosis. To address these issues, this grant proposes to work use the sponsorship of Dr. Diane Krause to clarify the role that BMSCs play in lung repair. Dr. Krause is a leader in this field whose successful mentoring has enabled her previous fellows to pursue academic careers. The aims herein will investigate the capacity of both transplanted and nontransplanted marrow to become lung epithelia and determine if BMSCs can transfer a functional gene to the respiratory epithelium. They also explore a role for the use of BMSCs to modulate the healing response in a fibrotic murine models of human lung disease. These questions will be explored using transgenic mouse models, single cell analysis of pneumocytes using flow cytometry and immunohistochemical techniques, assessment of marrow origin in situ hybridization, and analysis of stem cell contributions to lung repair on a number of biochemical, molecular and functional levels.